Abstract

Background

The development of analgesic tolerance following chronic morphine administration can
be a significant clinical problem. Preclinical studies demonstrate that chronic morphine
administration induces spinal gliosis and that inhibition of gliosis prevents the
development of analgesic tolerance to opioids. Many studies have also demonstrated
that ultra-low doses of naltrexone inhibit the development of spinal morphine antinociceptive
tolerance and clinical studies demonstrate that it has opioid sparing effects. In
this study we demonstrate that ultra-low dose naltrexone attenuates glial activation,
which may contribute to its effects on attenuating tolerance.

Results

Spinal cord sections from rats administered chronic morphine showed significantly
increased immuno-labelling of astrocytes and microglia compared to saline controls,
consistent with activation. 3-D images of astrocytes from animals administered chronic
morphine had significantly larger volumes compared to saline controls. Co-injection
of ultra-low dose naltrexone attenuated this increase in volume, but the mean volume
differed from saline-treated and naltrexone-treated controls. Astrocyte and microglial
immuno-labelling was attenuated in rats co-administered ultra-low dose naltrexone
compared to morphine-treated rats and did not differ from controls. Glial activation,
as characterized by immunohistochemical labelling and cell size, was positively correlated
with the extent of tolerance developed. Morphine-induced glial activation was not
due to cell proliferation as there was no difference observed in the total number
of glial cells following chronic morphine treatment compared to controls. Furthermore,
using 5-bromo-2-deoxyuridine, no increase in spinal cord cell proliferation was observed
following chronic morphine administration.

Conclusion

Taken together, we demonstrate a positive correlation between the prevention of analgesic
tolerance and the inhibition of spinal gliosis by treatment with ultra-low dose naltrexone.
This research provides further validation for using ultra-low dose opioid receptor
antagonists in the treatment of various pain syndromes.